Perspectives on Antiarrhythmic Drug Therapy: Disappointing Past, Current Efforts and Faint Hopes

Cardiac arrhythmia is a leading cause of morbidity and mortality, and the history of anti-arrhythmic drug therapies has been dismal. Development of apparently more and more selective and effective antiarrhythmic agents has been a focus of interest for drug research in the past few decades, however, neither the ideal compound, nor an optimal strategy could be demonstrated so far. Furthermore, disappointing results have been obtained with several old antiarrhythmic agents, like many class III and class I/C drugs as documented by the CAST and SWORD studies. Clearly, the direct proarrhythmic side-effects of many currently applied antiarrhythmic agents can not be overemphasized.

Better understanding of the proarrhythmic mechanisms may minimize these unwanted side-effects and yield better therapeutic results. Accordingly, having a deeper insight into the frequency-dependent properties of action potential morphology, the finely tuned myocardial Ca²⁺-handling, and the rate-dependence of antiarrhythmic drug action may improve our positions in the antiarrhythmic offensive. Similarly, refining our knowledge on pathological impulse generation, including the development of afterdepolarizations (EADs and DADs), and novel data on the sinoatrial pacemeaker function may help to develop more effective antiarrhythmic practices.

Since the cardiac electrogenesis is based on the well balanced function of ion channels mediating inward and outward currents, abnormal ion channels represent also important potential drug targets. At the same time, expression of altered ion channels in transgenic animal models is a promising new field of research. On the basis of above we can find new trails, new antiarrhythmic mechanisms (each of them, of course, will also carry its own pitfalls). Such novel strategy may be the selective suppression of late Na⁺ current, application of Na⁺/Ca²⁺ exchanger blockers, or manipulation of the gap junction conductance. All these topics are intimately discussed in this issue. Finally, the current state of clinical practice will be overviewed in terms of atrial and ventricular fibrillation, including the stunning problem of sudden cardiac death of athletes.

As the reader can suspect from the ideas above, the ideally omnipotent antiarrhythmic compound or strategy has not been developed so far, and most likely it will never be realized. The reason is theoretical rather than practical. Namely, that there are multiple mechanisms leading to cardiac arrhythmias, resulting very likely divergent consequences. The best example is the action potential duration itself. When it is too short, the chance of re-entry increases due to the short refractory period, while if it is too long, the risk of triggered activity rises. So it must be accepted that evolution had time enough to elaborate the optimal configuration of the cardiac action potential (ideal, of course, only under physiological conditions) and its modification may worsen arrhythmia incidence. It must be understood that we have a chance to find only better and more rational drugs and strategies, which may be considered only optimal, but not the ideal ones. However, due to the same reason, personalized antiarrhythmic treatment may best approximate these requirements.

In summary, this Research Topic is devoted to those areas of cardiac electrophysiology, pathophysiology and pharmacology which are critically important to improve the efficacy of antiarrhythmic treatment, carrying also important implications for future drug design.